Ovid Technologies (Wolters Kluwer Health)

Circulation

, volume 146 , issue 11 , pages 808-818

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF

Senthil Selvaraj ¹

Zhuxuan Fu ²

Philip G. Jones ²

Lydia Coulter Kwee ³

Sheryl L. Windsor ²

Olga Ilkayeva ^{3, 4}

Christopher B. Newgard ³

Kenneth B. Margulies ¹

Mansoor Husain ⁵

Silvio E. Inzucchi ⁶

Darren K. McGuire ⁷

BERTRAM PITT ⁸

Benjamin M. Scirica ⁹

David E. Lanfear ¹⁰

Michael E. Nassif ^{2, 11}

Ali Javaheri ¹²

Robert J. Mentz ¹³

Mikhail Kosiborod ^{2, 11}

Svati H. Shah ³

Hide authors affiliations Show authors affiliations: 13 affiliations

Division of Cardiology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia (S.S., K.B.M.). |

Saint Luke’s Mid America Heart Institute, Kansas City, MO (Z.F., P.J., S.L.W., M.E.N., M.N.K.). |

Duke Molecular Physiology Institute, Durham, NC (L.C.K., O.I., C.B.N., S.H.S.).

⁴

Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University School of Medicine, Durham, NC (O.I.). |

⁵

Ted Rogers Centre for Heart Research, University of Toronto, Canada (M.H.). |

⁶

Yale University School of Medicine, New Haven, CT (S.E.I.). |

⁷

University of Texas Southwestern Medical Center and Parkland Health and Hospital System, Dallas (D.K.M.). |

⁸

University of Michigan School of Medicine, Ann Arbor (B.P.). |

⁹

Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (B.M.S.).

Harvard University

Brigham and Women's Hospital

¹⁰

Center for Individualized and Genomic Medicine Research and Heart and Vascular Institute, Henry Ford Hospital, Detroit, MI (D.E.L.).

¹¹

University of Missouri–Kansas City (M.E.N., M.N.K.). |

¹²

Washington University School of Medicine, St Louis, MO (A.J.). |

¹³

Division of Cardiology, Duke University Medical Center, Durham, NC (R.J.M.). |

Publication type: Journal Article

Publication date: 2022-05-23

Ovid Technologies (Wolters Kluwer Health)

Circulation

scimago Q1

wos Q1

SJR: 8.668

CiteScore: 45.1

Impact factor: 38.6

ISSN: 00097322, 15244539

DOI: 10.1161/CIRCULATIONAHA.122.060402

Copy DOI

PubMed ID: 35603596

Cardiology and Cardiovascular Medicine

Physiology (medical)

Abstract

Background:

Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between sodium-glucose cotransporter-2 inhibitor treatment, changes in metabolic pathways, and outcomes using targeted metabolomics.

Methods:

DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis–defined metabolite clusters that changed differentially with treatment and examined the relationship between change in metabolite clusters and change in Kansas City Cardiomyopathy Questionnaire scores and NT-proBNP (N-terminal probrain natriuretic peptide). Models were adjusted for relevant clinical covariates and nominal P <0.05 with false discovery rate–adjusted P <0.10 was used to determine statistical significance.

Results:

Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short-chain acylcarnitine as well as medium-chain acylcarnitine principal components analysis–defined metabolite clusters compared with placebo (nominal P =0.01, false discovery rate–adjusted P =0.08 for both clusters). However, ketosis (β-hydroxybutyrate levels >500 μmol/L) was achieved infrequently (3 [2.5%] in dapagliflozin arm versus 1 [0.9%] in placebo arm) and supraphysiologic levels were not observed. Increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in Kansas City Cardiomyopathy Questionnaire scores (ie, worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group.

Conclusions:

In this study of targeted metabolomics in a placebo-controlled trial of sodium-glucose cotransporter-2 inhibitors in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with sodium-glucose cotransporter-2 inhibitors in patients with HFrEF. Only physiologic levels of ketosis were observed. In addition, we identified several metabolic biomarkers associated with adverse HFrEF outcomes.

Registration:

URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02653482.

Found

1 citation

Appolonova Svetlana

🤝

PhD in Chemistry

98 publications, 585 citations

h-index: 14

Sechenov First Moscow State Medical University

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GOST Copy

Selvaraj S. et al. Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF // Circulation. 2022. Vol. 146. No. 11. pp. 808-818.

GOST all authors (up to 50) Copy

Selvaraj S., Fu Z., Jones P. G., Kwee L. C., Windsor S. L., Ilkayeva O., Newgard C. B., Margulies K. B., Husain M., Inzucchi S. E., McGuire D. K., PITT B., Scirica B. M., Lanfear D. E., Nassif M. E., Javaheri A., Mentz R. J., Kosiborod M., Shah S. H. Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF // Circulation. 2022. Vol. 146. No. 11. pp. 808-818.

RIS |

Cite this

RIS Copy

TY - JOUR

DO - 10.1161/CIRCULATIONAHA.122.060402

UR - https://doi.org/10.1161/CIRCULATIONAHA.122.060402

TI - Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF

T2 - Circulation

AU - Selvaraj, Senthil

AU - Fu, Zhuxuan

AU - Jones, Philip G.

AU - Kwee, Lydia Coulter

AU - Windsor, Sheryl L.

AU - Ilkayeva, Olga

AU - Newgard, Christopher B.

AU - Margulies, Kenneth B.

AU - Husain, Mansoor

AU - Inzucchi, Silvio E.

AU - McGuire, Darren K.

AU - PITT, BERTRAM

AU - Scirica, Benjamin M.

AU - Lanfear, David E.

AU - Nassif, Michael E.

AU - Javaheri, Ali

AU - Mentz, Robert J.

AU - Kosiborod, Mikhail

AU - Shah, Svati H.

PY - 2022

DA - 2022/05/23

PB - Ovid Technologies (Wolters Kluwer Health)

SP - 808-818

IS - 11

VL - 146

PMID - 35603596

SN - 0009-7322

SN - 1524-4539

ER -

BibTex |

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BibTex (up to 50 authors) Copy

@article{2022_Selvaraj,

author = {Senthil Selvaraj and Zhuxuan Fu and Philip G. Jones and Lydia Coulter Kwee and Sheryl L. Windsor and Olga Ilkayeva and Christopher B. Newgard and Kenneth B. Margulies and Mansoor Husain and Silvio E. Inzucchi and Darren K. McGuire and BERTRAM PITT and Benjamin M. Scirica and David E. Lanfear and Michael E. Nassif and Ali Javaheri and Robert J. Mentz and Mikhail Kosiborod and Svati H. Shah},

title = {Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF},

journal = {Circulation},

year = {2022},

volume = {146},

publisher = {Ovid Technologies (Wolters Kluwer Health)},

month = {may},

url = {https://doi.org/10.1161/CIRCULATIONAHA.122.060402},

number = {11},

pages = {808--818},

doi = {10.1161/CIRCULATIONAHA.122.060402}

}

MLA

Cite this

MLA Copy

Selvaraj, Senthil, et al. “Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF.” Circulation, vol. 146, no. 11, May. 2022, pp. 808-818. https://doi.org/10.1161/CIRCULATIONAHA.122.060402.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Journal

Circulation

scimago Q1

wos Q1

SJR

8.668

CiteScore

45.1

Impact factor

38.6

ISSN

00097322 (Print)

15244539 (Electronic)

Profiles

Mansoor S Husain